Enhanced remodelable materials for occluding bodily vessels and related methods and systems

ABSTRACT

Described are methods, devices, and systems for occluding or ablating vascular vessels. Noninvasive procedures can be used to occlude and obliterate the greater saphenous vein, for example in the treatment of varicose vein condition caused by venous valve insufficiency. Further described is the cooperative use of an angiogenic remodelable material with one or more sclerosing agents to cause closure of a targeted bodily vessel.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/971,724, filed Sep. 12, 2007, entitled EnhancedRemodelable Materials for Occluding Bodily Vessels and Related Methodsand Systems, which is hereby incorporated herein in its entirety.

BACKGROUND

The present invention resides generally in the field of devices andmethods useful for the deployment of prosthetic devices, and in aparticular aspect relates to the deployment of prosthetic devices withinthe vasculature of a patient to treat complications, such as a varicosevein condition, resultant of venous reflux.

As further background, vascular vessels are comprised of tissue and arethe conduit for circulating blood through a mammalian body. A vascularvessel that carries blood from the heart is known as an artery. Avascular vessel that returns blood to the heart is known as a vein.There are three types of veins in a human: deep veins, which are locateddeep in the body close to the bones, superficial veins, which arelocated close to the skin, and perforating veins, which are smallerveins that connect the deep veins to the superficial veins.

To assist blood flow, venous vascular vessels contain venous valves.Each venous valve is located inside the vein and typically includes atleast two valve leaflets, which are disposed annularly along the insidewall of the vein. These leaflets open to permit blood flow toward theheart and close, upon a change in pressure, such as a transition fromsystole to diastole, to restrict the back flow of blood. When bloodflows towards the heart, the venous pressure forces the valve leafletsto move apart in a downstream flexing motion, thereby creating an openpath for blood flow. The leaflets normally flex together when moving inthe upstream direction; therefore, they return to a closed position torestrict or prevent blood flow in the upstream, or retrograde, directionafter the venous pressure is relieved. The leaflets, when functioningproperly, extend radially inward toward one another such that theleaflet tips, or cusps contact each other when the valve is closed.

On occasion, and for a variety of reasons, such as congenital valve orvein weakness, disease in the vein, obesity, pregnancy, and/or anoccupation requiring long periods of standing, one or more valves in avein will allow deleterious retrograde flow to occur. When a valveallows such retrograde flow, blood will collect, or pool in vesselsbeneath the valve. This pooling of blood causes an increase in thevenous pressure below the valve. Venous valves that allow suchdeleterious retrograde flow are known as incompetent or inadequatevenous valves. The condition resulting from such incompetent venousvalves is known as venous valve insufficiency.

In the condition of venous valve insufficiency, the venous valveleaflets do not function properly. Incompetent venous valves can causethe veins to bulge, can cause swelling in the patient's lowerextremities, and can result in varicose veins and/or chronic venousinsufficiency. If left untreated, venous valve insufficiency can causevenous stasis ulcers of the skin and subcutaneous tissue.

A common method of treatment for venous valve insufficiency is theplacement of an elastic stocking around the patient's leg to applyexternal pressure to the vein, forcing the walls radially inward toforce the leaflets into apposition. Although sometimes successful, thetight stocking is quite uncomfortable, especially in warm weather,because the stocking must be constantly worn to keep the leaflets inapposition. The elastic stocking also affects the patient's physicalappearance, thereby potentially having an adverse psychological affect.This physical and/or psychological discomfort can lead to the patientremoving the stocking, thereby inhibiting treatment.

Surgical methods for treatment of venous valve insufficiency have alsobeen developed. A vein with incompetent venous valves can be surgicallyconstricted to bring incompetent leaflets into closer proximity in hopesof restoring natural valve function. Methods for surgical constrictionof an incompetent vein include implanting a frame around the outside ofthe vessel, placing a constricting suture around the vessel (e.g.,valvuloplasty), or other types of treatment to the outside of the vesselto induce vessel contraction. Other surgical venous valve insufficiencytreatment methods include bypassing or replacing damaged venous valveswith autologous sections of veins containing competent valves.

Another surgical method includes vein stripping and ligation. In thisprocedure, the femoral vein and other major venous tributaries aredisconnected from the greater saphenous vein (GSV) and tied off. Next,the GSV is removed from the leg by advancing a wire through the vein,tying the wire to a saphenous vein end, and then pulling the wire, andvein, out through an incision in the upper calf or ankle. Unfortunately,the above surgeries require at least one incision and have severalundesirable side effects and risks, such as a long patient recoverytime, the potential for scarring, and numerous other risks inherent withsurgery, such as those associated with the administration of anesthesia.

Recently, various implantable prosthetic devices and minimally invasivemethods for implantation of these devices have been suggested to treatvenous valve insufficiency. Such prosthetic devices can be insertedintravascularly, for example from an implantation catheter. Prostheticdevices can function as a replacement venous valve, or enhance venousvalve function by bringing incompetent valve leaflets into closerproximity. In one procedure, venous valve function can be enhanced byclipping the valve leaflets together with a clip made from abiocompatible material, such as a metal or polymer.

Recently, a number of methods have been suggested to treat varicoseveins and venous valve leaflets with energy sources, such asradiofrequency (RF) energy. In one such method, valve leaflets can befastened together with electrodes delivering RF energy. In another suchmethod, a catheter having an electrode tip can be used to apply RFenergy to cause localized heating and corresponding shrinkage of venoustissue. After treatment of one venous section is complete, the cathetercan be repositioned to treat a different venous section.

Methods for treatment of varicose veins have also been developedinvolving various forms of sclerotherapy. Generally, sclerotherapyinvolves the delivery of one or more sclerosing agents to the lumen of avaricose, or other smaller diameter vein, which induce the vein tocollapse and the venous walls to fuse, thereby closing the vein.

In view of this background, the need remains for improved andalternative techniques, devices and systems for affecting the venoussystem to treat venous conditions. The present invention is addressed tothese needs.

SUMMARY OF THE INVENTION

Accordingly, in one aspect, the present invention provides a method forclosing a venous vessel that includes the cooperative emplacement of aremodelable material and one or more sclerosive agents within the venousvessel. The method includes injuring a venous wall segment with asclerosing agent and contacting an angiogenic remodelable material tothe injured venous tissue so as to occlude the vein in the treatment ofvenous valve insufficiency.

In another aspect, the present invention provides a medical product foroccluding a venous vessel that includes a remodelable material that isconfigured for deployment within a venous vessel and that is effectiveto promote the ingrowth of patient tissue into the lumen of the venousvessel. The remodelable material includes one or more sclerosants thatare effective to injure the lining of the venous vessel so as to enhancethe ingrowth of patient tissue into the remodelable material and promoteocclusion of the venous vessel.

In yet another aspect, the present invention provides a medical productfor occluding a bodily vessel that includes one or more sclerosingagents and an angiogenic remodelable material. The sclerosing agents andthe remodelable material are configured for conjunctive or cooperativeuse to enhance closure of the bodily vessel. Advantageous suchangiogenic remodelable materials can include extracellular matrixmaterials, such as porcine small intestine submucosa.

In still yet another aspect, the present invention provides a method foroccluding a venous vessel that includes providing a flowable remodelablematerial and one or more sclerosive agents. The flowable material isconfigured for placement within a venous vessel and is effective topromote the ingrowth of patient tissue within the lumen of the venousvessel. The sclerosive agents are configured for placement within thevenous vessel in conjunction with the provided flowable material and areeffective to injure the lining of the venous vessel. The method includeslocating the provided flowable material and the provided sclerosiveagents within the venous vessel wherein the material and agentscooperate to promote the closure and occlusion of the venous vessel.

In another aspect, the present invention provides a method for treatingvaricosities associated with venous valve insufficiency comprisingproviding a sponge form remodelable prosthesis that includes one or moresclerosive agents. The method continues by deploying the providedprosthesis within the greater or lesser saphenous vein of the patient soas to provide closure of the vein and treat varicosities associated withvenous valve insufficiency.

In yet another aspect, the present invention provides a medical kit thatincludes a medical product as discussed herein enclosed in sterilemedical packaging.

The present invention provides improved methods, system, and devices foroccluding venous and other bodily vessels. Additional embodiments aswell as features and advantages of the invention will be apparent fromthe further descriptions herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a human leg showing certain venous structures therein.

FIG. 2 depicts a human leg showing certain venous structures therein.

FIG. 3 depicts a human leg having an illustrative occlusion devicelocated in the greater saphenous vein.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to certain embodiments thereof andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations, further modificationsand further applications of the principles of the invention as describedherein being contemplated as would normally occur to one skilled in theart to which the invention relates.

As disclosed above, certain embodiments of the invention provide for thetreatment of venous valve insufficiency with the cooperative emplacementof a remodelable material and one or more sclerosants within a venousvessel, such as the greater saphenous vein. The method can includeinjuring a venous wall segment with a sclerosing agent and contacting anangiogenic remodelable material to the injured venous tissue so as toocclude the vein. The angiogenic remodelable material can include anextracellular matrix material, such as a sponge form material or aflowable material, and the sclerosive agent can be contained within thematerial, such as by soaking, mixing, or containing the sclerosive agentwithin the material, immediately prior to implantation, if desirable.

With reference now more particularly to the figures, shown in FIG. 1 isa diagram of a human leg showing certain venous structures therein. Inparticular, shown is human leg 200 having greater saphenous vein 10 andthe femoral vein 11 which adjoin at the sapheno-femoral junction 12. Inaccordance with certain aspects of the invention, greater saphenous vein10 can be occluded in a region constituting substantially all of thepassage between a point 13 occurring near the medial side of the knee toa point 14 occurring prior to the sapheno-femoral junction 12, asillustrated by the shaded area in FIG. 2. Desirably, such occlusion iseffective to prevent reflux of venous blood from the sapheno-femoraljunction 12 in a direction down toward the medial side of the knee (e.g.at point 13). Such occlusion is effective to treat varicosities thatcommonly occur in lower portions of the leg, e.g. portions occurringbelow the knee.

With reference now to FIG. 3, occlusion of the passage of the greatersaphenous vein occurring between points 13 and 14 can be achieved bycooperatively deploying an occlusive material 15 and one or moresclerosants from point 13 to point 14. In certain embodiments, theocclusive material may include an elongate sponge form material that mayinclude an end portion 16 that traverses the wall of the greatersaphenous vein 10. In alternative embodiments, the occlusive materialmay include a flowable remodelable material that can continuously orintermittently extend between points 13 and 14 within the greatersaphenous vein 10. Illustratively, the sclerosive material can becontained within the occlusive material at implantation, or can beemplaced within the vein 10 before, after, or during implantation of theocclusive material.

In an illustrative deployment procedure, percutaneous access to the GSVcan be achieved at point 13 using the Seldinger or any other suitabletechnique. For instance, an access needle can be passed through the skinto access the GSV 10, and a wire guide can be passed through the accessneedle and into the vein 10. Prior to the deployment of any occlusive orsclerosive material, the wire guide can be used for any number ofconventional procedures including catheterization and imaging proceduresto locate the sapheno-femoral junction 12, or vein dilation and/orstraightening procedures to prepare the vein for an occlusive implant.After any such preliminary procedures that are performed, the wire guidecan be used to place a cannulated delivery device within the vein 10.The wire guide can then be removed from the vein 10, thereby providingan open lumen through the cannulated device for delivery of one or moresclerosive agents and occlusive materials, as are discussed herein.

In illustrative embodiments, such as when the occlusive material has lowpushability or column strength, e.g. certain sponge form materials, aneverting delivery sheath, peel away sheath, or a sheath having areversible sleeve component can be used to deploy the occlusive devicewithin the vascular vessel 10. In such procedures, the occlusivematerial and sheath can be delivered using any suitable method, such asover a wire guide or through another cannulated device. In alternativeembodiments, such as when a foam material has sufficient columnstrength, the occluder, optionally containing a sclerosant, can beintroduced into the vein and thereafter openly advanced (without asheath) through the vein to implant the device, over a guide wire ifdesirable. In still alternative embodiments, such as when percutaneousaccess is undesirable, the sclerosive agents and certain flowableocclusive materials can be injected at one or more locations betweenpoints 13 and 14 within the GSV 10 using one or more needle/syringecombinations until suitable occlusion is achieved. For more informationconcerning suitable endoluminal delivery techniques, reference can bemade, for example to U.S. Pat. Pub. No. 2003/0051735 and/orWO2005/053547.

Turning now to a discussion of occlusive device materials, illustrativesuch materials can include any suitable biocompatible material.Generally, the occlusion materials may include synthetic materials orreconstituted or naturally-derived collagenous materials. Suchbiocompatible materials that are at least bioresorbable will provideadvantage in embodiments of the invention, with materials that arebioremodelable and promote cellular invasion and ingrowth providingparticular advantage. Illustratively, remodelable materials may be usedin this context to promote cellular growth within the occlusivematerials to promote the closure of an occluded passageway.

Bioremodelable materials of the invention can be provided by collagenousextracellular matrix (ECM) materials possessing biotropic properties,including in certain forms angiogenic collagenous ECM materials. Forexample, suitable collagenous materials include ECM materials, such assubmucosa, renal capsule membrane, dermal collagen, dura mater,pericardium, serosa, facia lata, peritoneum, or basement membrane layersincluding liver basement membrane. The preferred medical graft productsof the invention will include submucosa, such as submucosa derived froma warm-blooded vertebrate. Suitable submucosa materials for thesepurposes include, for instance, intestinal submucosa, including smallintestinal submucosa, stomach submucosa, urinary bladder submucosa, anduterine submucosa. Mammalian submucosa materials are preferred. Inparticular, submucosa materials derived from animals raised for meat orother product production, e.g. pigs, cattle or sheep, will beadvantageous. Porcine submucosa provides a particularly preferredmaterial for use in the present invention, especially porcine smallintestine submucosa (SIS), more especially porcine small intestinesubmucosa retaining substantially its native cross-linking.

The submucosa or other ECM material can be derived from any suitableorgan or other biological structure, including for example submucosaderived from the alimentary, respiratory, intestinal, urinary or genitaltracts of warm-blooded vertebrates. Submucosa useful in the presentinvention can be obtained by harvesting such tissue sources anddelaminating the submucosa from smooth muscle layers, mucosal layers,and/or other layers occurring in the tissue source. For additionalinformation concerning submucosa useful in certain embodiments of thepresent invention, and its isolation and treatment, reference can bemade, for example, to U.S. Pat. Nos. 4,902,508, 5,554,389, 5,993,844,6,206,931, and 6,099,567.

Submucosa or other ECM materials can be derived from any suitable organor other tissue source, usually sources containing connective tissues.The ECM materials processed for use in certain embodiments willtypically include abundant collagen, most commonly being constituted ofat least about 80% by weight collagen on a dry weight basis. Suchnaturally-derived ECM materials will for the most part include collagenfibers that are non-randomly oriented, for instance occurring asgenerally uniaxial or multi-axial but regularly oriented fibers. Whenprocessed to retain native bioactive factors, the ECM material canretain these factors interspersed as solids between, upon and/or withinthe collagen fibers. Particularly desirable naturally-derived ECMmaterials for use in embodiments of the invention will includesignificant amounts of such interspersed, non-collagenous solids thatare readily ascertainable under light microscopic examination. Suchnon-collagenous solids can constitute a significant percentage of thedry weight of the ECM material in certain embodiments, for example atleast about 1%, at least about 3%, and at least about 5% by weight invarious embodiments of the invention.

The submucosa or other ECM material used in illustrative embodiments mayalso exhibit an angiogenic character and thus be effective to induceangiogenesis in a host engrafted with the material. In this regard,angiogenesis is the process through which the body makes new bloodvessels to generate increased blood supply to tissues. Thus, angiogenicmaterials, when contacted with host tissues, promote or encourage theformation of new blood vessels. Methods for measuring in vivoangiogenesis in response to biomaterial implantation have recently beendeveloped. For example, one such method uses a subcutaneous implantmodel to determine the angiogenic character of a material. See, C.Heeschen et al., Nature Medicine 7 (2001), No. 7, 833-839. When combinedwith a fluorescence microangiography technique, this model can provideboth quantitative and qualitative measures of angiogenesis intobiomaterials. C. Johnson et al., Circulation Research 94 (2004), No. 2,262-268.

As prepared and used, the submucosa material or any other ECM materialmay optionally retain and/or include growth factors or other bioactivecomponents native to the source tissue. For example, the submucosa orother ECM material may include one or more growth factors such as basicfibroblast growth factor (FGF-2), transforming growth factor beta(TGF-beta), epidermal growth factor (EGF), and/or platelet derivedgrowth factor (PDGF). As well, submucosa or other ECM material used inembodiments of the invention may include other biological materials suchas heparin, heparin sulfate, hyaluronic acid, fibronectin and the like.Thus, generally speaking, the submucosa or other ECM material mayinclude a bioactive component that induces, directly or indirectly, acellular response such as a change in cell morphology, proliferation,growth, protein or gene expression. In certain preferred embodiments ofthe invention, the ECM material will exhibit the capacity to promoteangiogenesis.

Further, in addition or as an alternative to the inclusion of nativebioactive components, non-native bioactive components such as thosesynthetically produced by recombinant technology or other methods, maybe incorporated into the submucosa or other ECM material. Thesenon-native bioactive components may be naturally-derived orrecombinantly produced proteins that correspond to those nativelyoccurring in the ECM material, but perhaps of a different species (e.g.human proteins applied to collagenous ECMs from other animals, such aspigs). The non-native bioactive components may also be drug substances.Illustrative drug substances that may be incorporated into and/or ontothe ECM material can include, for example, antibiotics and/orthrombus-promoting substances such as blood clotting factors, e.g.thrombin, fibrinogen, and the like. These substances may be applied tothe ECM material as a premanufactured step, immediately prior to theprocedure (e.g. by soaking the material in a solution containing asuitable antibiotic such as cefazolin), or during or after engraftmentof the ECM material within the patient.

Submucosa or other ECM material used in embodiments of the invention ispreferably highly purified, for example, as described in U.S. Pat. No.6,206,931 to Cook et al. Thus, preferred ECM material will exhibit anendotoxin level of less than about 12 endotoxin units (EU) per gram,more preferably less than about 5 EU per gram, and most preferably lessthan about 1 EU per gram. As additional preferences, the submucosa orother ECM material may have a bioburden of less than about 1 colonyforming units (CFU) per gram, more preferably less than about 0.5 CFUper gram. Fungus levels are desirably similarly low, for example lessthan about 1 CFU per gram, more preferably less than about 0.5 CFU pergram. Nucleic acid levels are preferably less than about 5 μg/mg, morepreferably less than about 2 μg/mg, and virus levels are preferably lessthan about 50 plaque forming units (PFU) per gram, more preferably lessthan about 5 PFU per gram. The ECM material used in embodiments of theinvention is preferably disinfected with an oxidizing agent,particularly a peracid, such as peracetic acid. These and additionalproperties of submucosa or other ECM materials taught in U.S. Pat. No.6,206,931 may be characteristic of the submucosa used in aspects of thepresent invention.

Turning now to a discussion of three-dimensionally stable materials,e.g. foam or sponge form materials, that can be used to form occlusivedevices, such materials may include any suitable biocompatible material.Illustrative sponge or foam matrices will generally comprise porous,three-dimensionally stable bodies formed from suitable biocompatiblematrix materials. For example, suitable biocompatible matrix materialsinclude naturally-occurring polymers and/or synthetic polymers ormaterials, such as hydrogels, gel foam, and/or polyvinyl (alcohol) foam.More preferred sponge compositions will comprise collagen as amatrix-forming material, either alone or in combination with one or moreother matrix forming materials. In general, sponge matrices useful inembodiments of the invention can be formed by providing a liquidsolution or suspension of a matrix-forming material, and causing thematerial to form a porous three-dimensionally stable structure; however,a sponge or foam material can be formed using any suitable formationmethod, as is known in the art.

Illustratively, in the formation of a collagenous sponge or foammaterial, a collagen solution or suspension can be prepared. Thecollagen may be derived from mammalian or other animal sources, forexample, bovine, porcine or human sources, and desirably is derived fromremodelable ECM materials as discussed herein. Synthetically-derivedcollagen may also be used. The determination of suitable collagenconcentrations in the solution will be within the purview of thoseskilled in the art, with concentration ranges of about 0.05 g/ml toabout 0.2 g/ml being typical.

Digestion of the collagen to form the collagen solution is usuallycarried out under acidic conditions, starting with ground, minced orotherwise comminuted collagen-containing tissue. Optionally, enzymaticdigestion may be utilized using known enzymes for this purpose such aspepsin, trypsin, and/or papain. After digestion, the enzymes can beremoved by suitable, known techniques.

The collagenous solution and/or suspension can be employed as a moldableor castable material in the formation of the foam or sponge. The castmaterial can be dried directly without chemical crosslinking or can becrosslinked with a suitable crosslinking agent and then dried.Illustrative crosslinking agents for these purposes includeglutaraldehyde, formaldehyde, carbodiimides, UV irradiation, or othercrosslinking agents. In preferred embodiments, the crosslinking agentwill contain polar groups that impart a hydrophilic character to thefinal sponge matrix material. Desirably, a polyepoxide crosslinker isutilized for this purpose, especially a polyglycidyl ether compound.Suitable such compounds include ethylene glycol diglycidyl ether,available under the trade name Denacol EX810 from Nagese Chemical Co.,Osaka, Japan, and glycerol polyglycidyl ether available under the tradename Denacol EX313 also from Nagese Chemical Co. Typically, polyglycidylethers or other polyepoxide compounds utilized in the invention willhave from 2 to about 10 epoxide groups per molecule. The use of suchepoxides and/or other crosslinking agents which impart polar groups anda hydrophilic character to the resulting matrix will provide for goodwettability and rapid hydration and expansion of closure devices of theinvention.

Preferred sources of collagen for forming illustrative sponge matricesinclude extracellular matrix materials as discussed herein, such ascollagenous submucosal tissues, and other collagenous basement membranematerials. These include, for example, small intestinal submucosa,stomach submucosa, urinary bladder submucosa, liver basement membrane,and other basement membrane materials. For additional information as tothese collagenous matrix materials and their preparation, reference canbe made for example to U.S. Pat. Nos. 4,511,653, 4,902,508, 4,956,178,5,554,389, and 6,099,567, 6,206,931, and International Publication Nos.WO9825637 and WO9822158, each of which is hereby incorporated herein byreference in its entirety. In forming sponge matrices, these materialsare preferably processed and utilized under conditions which retaintheir favorable growth properties. This may include, for example,processing under conditions in which native proteins and/or othermaterials, for instance biotropic agents, are retained in theirbioactive form. For example, the collagen sources, and resulting spongematrices, may include active native substances such as one or moregrowth factors, e.g. basic fibroblast growth factor (FGF-2);transforming growth factor beta (TGF-beta); epidermal growth factor(EFG); platelet derived growth factor (PDGF); and/or other substancessuch as glycosaminoglycans (GAGs); and/or fibronectin (FN).

Sponge matrix materials that can be used to form illustrative devicescan be highly expandable when wetted, so as to achieve an expandedconfiguration. Illustratively, expandable sponge materials can exhibitthe capacity to expand at least 100% by volume, more preferably at leastabout 200% by volume, and typically in the range of about 300% by volumeto about 1000% by volume, when wetted to saturation with deionizedwater. Sponge materials used in aspects of the invention can alsoexhibit advantageous rates of expansion, achieving volume expansions asnoted above in less than about 10 seconds, more preferably less thanabout 5 seconds, when immersed in deionized water.

Highly compact, dense sponge matrices can be prepared by first hydratingor otherwise wetting a porous sponge matrix, and then compressing anddrying the element. Such preparative processes generally provide a moredense, rigid and stably compressed sponge matrix than processes such assimple compaction of the dry sponge matrix. Drying can be conductedsufficiently to stabilize the sponge matrix. For example, preferreddrying procedures will reduce the liquid (e.g. water) content of thematrix to less than about 20% by weight, more preferably less than about10% by weight. Compression forces can be applied so as to achieve afinal density and/or desirable configuration, and can be applied in one,two or three dimensions, including radially, such as can be provided bya radial compression device. The drying of the compacted element caninvolve lyophilization (or freeze drying) or vacuum drying at ambient orelevated temperatures. When processed in this fashion, upon removal ofthe compaction force, the sponge matrix is stabilized structurally andremains in its highly dense and compacted state until contacted with aliquid susceptible to absorption by the matrix, for example body fluids.The pores of the matrix are thereby stably retained at a volumesubstantially reduced from their maximum volume, but return to apartially or fully expanded state when the matrix material is wetted.

Compressed sponge matrices forming occlusive bodies of the invention canbe highly dense, typically having densities of at least about 0.05g/cm³, preferably in the range of about 0.05 g/cm³ to about 0.2 g/cm³,and more preferably about 0.075 g/cm³ to about 0.2 g/cm³. The compactedsponge matrix can have sufficient column strength to be deployed bypassage through needles, catheters, sheaths, or bodily vessels forexample by utilizing a push rod or other pusher element (gloved hand) toforce the sponge matrix body through the vessel, needle and/or cathetercannula. Expanded sponge densities (dry) will generally be less than thecorresponding compacted densities. Typical expanded densities (dry) willrange from about 0.01 g/cm³ to about 0.1 g/cm³, more preferably about0.02 g/cm³ to about 0.07 g/cm³.

Compressed sponge materials may also contain agents which promotefurther retention of the compressed, high density form of the matrices.These may include for example starch, cellulose, sugars such asdextrose, or glycerin. Such agents can optionally be included in theliquid (preferably aqueous) used to hydrate or otherwise wet the spongeprior to compaction and drying. For additional information on certainfoam or sponge form materials, reference can be made, for example, toU.S. Pat. App. Pub. No. 2003/0013989.

In additional embodiments, occlusion devices of the invention can bemade from ECM's or other collagenous materials that have been subjectedto processes that expand the materials. In certain forms, such expandedmaterials can be formed by the controlled contact of an ECM materialwith one or more alkaline substances until the material expands, and theisolation of the expanded material. Illustratively, the contacting canbe sufficient to expand the ECM material to at least 120% of (i.e. 1.2times) its original bulk volume, or in some forms to at least about twotimes its original volume. Thereafter, the expanded material canoptionally be isolated from the alkaline medium, e.g. by neutralizationand/or rinsing. The collected, expanded material can be used in anysuitable manner in the preparation of a graft device. Illustratively,the expanded material can be enriched with bioactive components, dried,and/or molded, etc., in the formation of a graft construct of a desiredshape or configuration. In certain embodiments, a dried graft constructformed with the expanded ECM material can be highly compressible (orexpandable) such that the material can be compressed for delivery, suchas from within the lumen of a cannulated delivery device, and thereafterexpand upon deployment from the device so as to become anchored within apatient and/or cause closure of a bodily segment within the patient.

Expanded collagenous or ECM materials can be formed by the controlledcontact of a collagenous or ECM material with an aqueous solution orother medium containing sodium hydroxide. Alkaline treatment of thematerial can cause changes in the physical structure of the materialthat in turn cause it to expand. Such changes may include denaturationof the collagen in the material. In certain embodiments, it is preferredto expand the material to at least about three, at least about four, atleast about 5, or at least about 6 or even more times its original bulkvolume. The magnitude of the expansion is related to several factors,including for instance the concentration or pH of the alkaline medium,exposure time, and temperature used in the treatment of the material tobe expanded.

ECM materials that can be processed to make expanded materials caninclude any of those disclosed herein or other suitable ECM'S. Typicalsuch ECM materials will include a network of collagen fibrils havingnaturally-occurring intramolecular cross links and naturally-occurringintermolecular cross links. Upon expansion processing as describedherein, the naturally-occurring intramolecular cross links andnaturally-occurring intermolecular cross links can be retained in theprocessed collagenous matrix material sufficiently to maintain thecollagenous matrix material as an intact collagenous sheet material;however, collagen fibrils in the collagenous sheet material can bedenatured, and the collagenous sheet material can have analkaline-processed thickness that is greater than the thickness of thestarting material, for example at least 120% of the original thickness,or at least twice the original thickness.

Illustratively, the concentration of the alkaline substance fortreatment of the remodelable material can be in the range of about 0.5to about 2 M, with a concentration of about 1 M being more preferable.Additionally, the pH of the alkaline substance can in certainembodiments range from about 8 to about 14. In preferred aspects, thealkaline substance will have a pH of from about 10 to about 14, and mostpreferably of from about 12 to about 14.

In addition to concentration and pH, other factors such as temperatureand exposure time will contribute to the extent of expansion, asdiscussed above. In this respect, in certain variants, the exposure ofthe collagenous material to the alkaline substance is performed at atemperature of about 4 to about 45° C. In preferred embodiments, theexposure is performed at a temperature of about 25 to about 40° C., with37° C. being most preferred. Moreover, the exposure time can range fromat least about one minute up to about 5 hours or more. In someembodiments, the exposure time is about 1 to about 2 hours. In aparticularly preferred embodiment, the collagenous material is exposedto a 1 M solution of NaOH having a pH of 14 at a temperature of about37° C. for about 1.5 to 2 hours. Such treatment results in collagendenaturation and a substantial expansion of the remodelable material.Denaturation of the collagen matrix of the material can be observed as achange in the collagen packing characteristics of the material, forexample a substantial disruption of a tightly bound collagenous networkof the starting material. A non-expanded ECM or other collagenousmaterial can have a tightly bound collagenous network presenting asubstantially uniform, continuous surface when viewed by the naked eyeor under moderate magnification, e.g. 100× magnification. Conversely, anexpanded collagenous material can have a surface that is quitedifferent, in that the surface is not continuous but rather presentscollagen strands or bundles in many regions that are separated bysubstantial gaps in material between the strands or bundles when viewedunder the same magnification, e.g. about 100x. Consequently, an expandedcollagenous material typically appears more porous than a correspondingnon-expanded collagenous material. Moreover, in many instances, theexpanded collagenous material can be demonstrated as having increasedporosity, e.g. by measuring for an increased permeability to water orother fluid passage as compared to the non-treated starting material.The more foamy and porous structure of an expanded ECM or othercollagenous material can allow the material to be cast or otherwiseprepared into a variety of three-dimensionally stable shapes for use inthe preparation of medical materials and devices. It can further allowfor the preparation of constructs that are highly compressible and whichexpand after compression. Such properties can be useful, for example,when the prepared graft construct is to be compressed and loaded into adeployment device (e.g. a lumen thereof) for delivery into a patient,and thereafter deployed to expand at the implant site.

After such alkaline treatments, the material can be isolated from thealkaline medium and processed for further use. Illustratively, thecollected material can be neutralized and/or rinsed with water to removethe alkalinity from the material, prior to further processing of thematerial to form a graft construct.

A starting ECM material (i.e., prior to treatment with the alkalinesubstance) can optionally include a variety of bioactive or othernon-collagenous components including, for example, growth factors,glycoproteins, glycosaminoglycans, proteoglycans, nucleic acids, andlipids. Treating the material with an alkaline substance may reduce thequantity of one, some or all of such non-collagenous componentscontained within the material. In certain embodiments, controlledtreatment of the remodelable material with an alkaline substance will besufficient to create a remodelable collagenous material which issubstantially devoid of nucleic acids and lipids, and potentially alsoof growth factors, glycoproteins, glycosaminoglycans, and proteoglycans.

In certain embodiments, one or more bioactive components, exogenous orendogenous, for example, similar to those removed from an expandedmaterial during alkaline processing, can be returned to the material.For example, an expanded material can include a collagenous materialwhich has been depleted of nucleic acids and lipids, but which has beenreplenished with growth factors, glycoproteins, glycosaminoglycans,and/or proteoglycans. These bioactive components can be returned to thematerial by any suitable method. For instance, in certain forms a tissueextract, such as is discussed in U.S. Pat. No. 6,375,989 which is herebyincorporated herein by reference in its entirety, containing thesecomponents can be prepared and applied to an expanded collagenousmaterial. In one embodiment, the expanded collagenous material can beincubated in a tissue extract for a sufficient time to allow bioactivecomponents contained therein to associate with the expanded collagenousmaterial. The tissue extract may, for example, be obtained fromnon-expanded collagenous tissue of the same type used to prepare theexpanded material. Other means for returning or introducing bioactivecomponents to an expanded remodelable collagenous material includespraying, impregnating, dipping, etc. as known in the art. By way ofexample, an expanded collagenous material may be modified by theaddition of one or more growth factors such as basic fibroblast growthfactor (FGF-2), transforming growth factor beta (TGF beta), epidermalgrowth factor (EGF), platelet derived growth factor (PDGF), and/orcartilage derived growth factor (CDGF). As well, other biologicalcomponents may be added to an expanded collagenous material, such asheparin, heparin sulfate, hyaluronic acid, fibronectin and the like.Thus, generally speaking, an expanded collagenous material may include abioactive component that induces, directly or indirectly, a cellularresponse such as a change in cell morphology, proliferation, growth,protein or gene expression.

Expanded collagenous materials can be used to prepare a wide variety ofocclusive devices. Methods for preparing such occlusive devices caninclude contacting an ECM or other collagenous starting material with analkaline substance in an amount effective to expand the material,casting or otherwise forming the expanded collagenous material into anocclusive shape (e.g. an elongate tube or cylinder), and lyophilizingthe expanded material to form a dried occlusive device.

Turning now to a more detailed discussion of flowable occlusivematerials for use in aspects of the invention, such flowable materialscan include any suitable biocompatible flowable material that willpromote the closure of a venous vessel. For example, a flowableextracellular matrix material can be used to fill bodily vessels andpromote tissue ingrowth to close the vessels. In this regard, theflowable material can be delivered in any suitable fashion, includingfor example forcible ejection from cannulated members such as catheters,sheaths, or needles. Suitable flowable, remodelable ECM materials foruse in these aspects of the invention can be prepared, for example, asdescribed in U.S. Pat. Nos. 5,275,826, 5,516,533, 6,206,931, 6,444,229and/or in International Publication No. WO2005020847 (Cook BiotechIncorporated) published Mar. 10, 2005, which are each herebyincorporated by reference in their entirety.

Such flowable materials can include solubilized and/or particulate ECMcomponents, and in preferred forms include ECM gels having suspendedtherein ECM particles, for example having an average particle size ofabout 50 microns to about 500 microns, more preferably about 100 micronsto about 400 microns. The ECM particulate can be added in any suitableamount relative to the solubilized ECM components, with preferred ECMparticulate to ECM solubilized component weight ratios (based on drysolids) being about 0.1:1 to about 200:1, more preferably in the rangeof 1:1 to about 100:1. The inclusion of such ECM particulates in theultimate gel can serve to provide additional material that can functionto provide bioactivity to the gel (e.g. itself including FGF-2 and/orother growth factors or bioactive substances as discussed herein) and/orserve as scaffolding material for tissue ingrowth. Flowable ECMmaterials can also be used in conjunction with other occlusive devicesas described herein, or otherwise.

For example, a flowable material can be emplaced with a formed occlusiveconstruct, such as to help seal any voids between the construct and avessel wall or to provide a cap at one or both device ends.Additionally, flowable material, optionally containing agents (asdiscussed herein), may be emplaced in between two or more otherocclusive constructs to fill any desired amount of vessel space betweenthe formed devices. Still additionally, one or more agents (or asolution thereof) can be placed in between two or more occlusiveconstructs (including a bolus of flowable ECM material) in a commonbodily vessel to promote occlusion thereof. For more informationconcerning the emplacement of occlusive materials, reference can bemade, for example to U.S. Pat. No. 5,456,693, which is herebyincorporated herein by reference.

Turning now to a discussion of certain synthetic materials, such asfabrics, that can be formed or incorporated into occlusive constructsfor use in embodiments of the invention, such synthetic materials mayinclude nonresorbable synthetic biocompatible polymers, such ascellulose acetate, cellulose nitrate, silicone, polyethyleneteraphthalate, polyurethane, polyamide, polyester, polyorthoester,polyanhydride, polyether sulfone, polycarbonate, polypropylene, highmolecular weight polyethylene, polytetrafluoroethylene, or mixtures orcopolymers thereof. Illustrative resorbable synthetic materials caninclude polylactic acid, polyglycolic acid or copolymers thereof, apolyanhydride, polycaprolactone, polyhydroxy-butyrate valerate,polyhydroxyalkanoate, or another biodegradable polymer or mixturethereof. For further information concerning suitable synthetic materials(both biodegradable and nonbiodegradable), useful in certain embodimentsof the invention, reference can be made, for example, to U.S. UtilityPat. App. No. 2005/0228486 entitled, “Implantable Frame with VariableCompliance,” filed on Apr. 11, 2005.

Turning now to a discussion of certain agents that can be conjunctivelyor cooperatively used with occlusive materials to provide for theclosure of bodily vessels, such agents can include any substance that iscapable of bringing about or inducing constriction, spasm, or closure ina bodily vessel of a patient and/or causing the de-epithelialization orinflammation (either dilative or constrictive), and/or initiating ahealing response in certain patient tissue, such as a wall segment of avenous vessel. Illustrative such agents can include any suitablevasoconstrictive agent, sclerosive agent, thrombogenic agent,inflammatory agent, hypercoagulable agent, or any suitable combinationof one or more of any of the above or other suitable agents. Forexample, suitable vasoconstrictive agents can include any suitable alphaadrenergic direct or indirect agonist, such as norepinephrine,epinephrine, phenylephrine, and/or cocaine, or lidocaine, hypertonicsaline, or any suitable combination thereof. Illustrative sclerosiveagents can include, for example, polidocanol, sodium tetradecyl sulfate,e.g. SOTRADECOL®, morrhuate sodium, ethanolamine oleate, tetradecylsulfate, tetracycline, glycerin, hypertonic glucose, talc, acetic acid,alcohol, bleomycin, picibanil, ethibloc, deoxycycline, and/or anysuitable microfoam that contains a sclerosive agent, such as VARISOLVE®,manufactured by Provensis, Ltd. of London, England, or any othersuitable agent as disclosed in U.S. Pat. Nos. 5,676,962 and/or6,572,873, for example, each of which is hereby incorporated herein inits entirety.

Turning now to a general discussion of occlusive constructs useful inembodiments of the invention and certain methods for making and usingthe same, illustrative such devices can include any material, expandableor non, that occupies a volumetric shape or space that is suitable forpromoting closure of a vascular or other bodily vessel. Illustratively,such occlusive devices can include one or more boluses of a flowableremodelable material placed within a bodily lumen and/or an elongatesponge form material and/or any other suitable volumetric construct,such as can be formed by folding or rolling, or otherwise overlaying oneor more portions of a biocompatible sheet material, for example. Asdiscussed below, in embodiments, the overlaid sheet material or onlyportions or segments thereof, can be compressed and dried or otherwisebonded such that an occlusive construct, e.g. a substantially unitaryconstruct, is formed. The occlusive construct can then be placed withina vascular vessel in a manner such that the construct fills at least aluminal segment of the vessel.

Occlusive constructs can include multilaminate materials, such as sheetform material or volumetric constructs formed from such multilaminatematerials. To form a multilaminate construct, two or more ECM segmentscan be rolled or stacked, or one ECM segment folded over itself at leastone time, and then the layers can be fused or bonded together using abonding technique, such as chemical cross-linking or vacuum pressingduring dehydrating conditions.

An adhesive, glue or other bonding agent may also be used in achieving abond between ECM layers. Suitable bonding agents may include, forexample, collagen gels or pastes, gelatin, or other agents includingreactive monomers or polymers, for example cyanoacrylate adhesives. Aswell, bonding can be achieved or facilitated using chemicalcross-linking agents, such as glutaraldehyde, formaldehyde, epoxides,genipin or derivatives thereof, carbodiimide compounds, polyepoxidecompounds, or other similar agents, including those others identified inthe discussions above. Cross-linking of ECM materials can also becatalyzed by exposing the matrix to UV radiation, by treating thecollagen-based matrix with enzymes such as transglutaminase and lysyloxidase, and by photocross-linking. The combination of one or more ofthese with dehydration-induced bonding may also be used.

A variety of dehydration-induced bonding methods can be used to fuse ECMportions of the bioremodelable material. In one preferred embodiment,the multiple layers of ECM material are compressed under dehydratingconditions. The term “dehydrating conditions” can include any mechanicalor environmental condition which promotes or induces the removal ofwater from the ECM material. To promote dehydration of the compressedECM material, at least one of the two surfaces compressing the matrixstructure can be water permeable. Dehydration of the ECM material canoptionally be further enhanced by applying blotting material, heatingthe matrix structure or blowing air, or other inert gas, across theexterior of the compressing surfaces. One particularly useful method ofdehydration bonding ECM materials is lyophilization, e.g. freeze-dryingor evaporative cooling conditions.

Another method of dehydration bonding comprises pulling a vacuum on theassembly while simultaneously pressing the assembly together. Thismethod is known as vacuum pressing. During vacuum pressing, dehydrationof the ECM materials in forced contact with one another effectivelybonds the materials to one another, even in the absence of other agentsfor achieving a bond, although such agents can be used while also takingadvantage at least in part of the dehydration-induced bonding. Withsufficient compression and dehydration, the ECM materials can be causedto form a generally unitary ECM structure.

It is advantageous in some aspects of the invention to perform dryingoperations under relatively mild temperature exposure conditions thatminimize deleterious effects upon the ECM materials of the invention,for example native collagen structures and potentially bioactivesubstances present. Thus, drying operations conducted with no orsubstantially no duration of exposure to temperatures above human bodytemperature or slightly higher, say, no higher than about 38° C., willpreferably be used in some forms of the present invention. Theseinclude, for example, vacuum pressing operations at less than about 38°C., forced air drying at less than about 38° C., or either of theseprocesses with no active heating—at about room temperature (about 25°C.) or with cooling. Relatively low temperature conditions also, ofcourse, include lyophilization conditions.

In additional embodiments, illustrative occlusive constructs of theinvention can be formed by randomly or regularly packing one or morepieces of single or multilayer ECM sheet material within a mold andthereafter processing the packed material. Such suitable processing caninclude, for example, providing the packed ECM sheet material in apartially or otherwise completely wetted or hydrated form and cancomplete, at least in part, by partially or completely dehydrothermallybonding the hydrated packed sheet material to establish a substantiallyunitary construct. Illustratively, for example, a randomly packedconstruct can be formed by placing folded, wadded, gathered, orotherwise packed ECM sheet material within a mold, and thereafter dryingthe randomly configured material to form a substantially unitaryocclusive construct.

Packed, molded graft constructs can also include suitable flowable,comminuted, and/or sponge form materials, each of which can be ECMbased, interspersed within rolled, folded, or otherwise randomly packedand/or covered ECM material. Additionally, these materials can be formedinto any suitable shape, configuration, size and/or length as disclosedherein.

Illustratively, such cast occlusive constructs may include one or moresurface protuberances and/or perforations. Such protuberances mayinclude a plurality of such protuberances axially aligned on the surfaceat one or more locations, e.g. two. Such protuberances may correspondwith apertures in the mold used to form the occlusive construct, suchprocedures typically including a drying or bonding step, e.g.lyophilization. Such perforations will typically at least partiallypenetrate a transverse length of occlusive construct's body, and incertain embodiments will completely transversely penetrate the occlusiveconstructs body. Such perforations may form a plurality of surfaceapertures on the construct, which may be axially aligned at one or morelocations, e.g. two, and in certain embodiments such apertures cancorrespond with at least a portion of such protuberances. Suchperforations may be initially formed as part of the process of makingthe occlusive constructs, such as prior to or during a drying step, e.g.lyophilization, and as such, certain segments of the perforated tractmay close as the manufacture of the product completes. For moreinformation regarding volumetric constructs, as well as surfaceprotuberances and body apertures, reference can be made, for example, toU.S. patent application Ser. No. 11/415,403, entitled “VOLUMETRIC GRAFTSFOR THE TREATMENT OF FISTULAE AND RELATED METHODS AND SYSTEMS,” filedMay 1, 2006, which is hereby incorporated by reference in its entirety.

Occlusive devices for use in aspects of the invention may include anyocclusive device that is pushable or guidable through a bodily vessel orbodily lumen as discussed herein and that will close or occlude thevessel after implantation. Illustrative such devices can occupy anysuitable volumetric shape, form, size, and material. Such devices caninclude single or multilaminate sheet material, such as in a fan foldedconfiguration that can be delivered and deployed at an implantation sitein a folded over, such as folded in half lengthwise, configuration.Additional such guidable devices can include elongate sponge formdevices that can be delivered and deployed in a folded-over, such asfolded in half over a deployment device, or non-folded configuration.Illustrative such self guidable devices can include an expandable spongeform material having sufficient column strength such that it isadvancable through a vein or other vascular vessel. Alternative suchself-guidable devices can include a sheet material that is processed toitself such that it provides sufficient stiffness to the material to beadvancable through a vein or other bodily vessel, or a material thatincorporates certain rigid or semi-rigid materials or objects thatenhance the stiffness of the occlusive material to make the materialguidable through a bodily lumen.

In this regard, suitable such self guidable devices can includeocclusive devices that exhibit a column strength, such as describedherein, that includes any value between about 200 kPA or less to about12,000 kPA or more. Additional such column strengths can include anyvalue within the range of from about 700 kPA to about 11,000 kPA, andstill additional such column strengths may include any value from about1,000 kPA to about 10,000 kPA. Illustrative such column strength valuescan be measured using an Instron compressive strength testing machine. Asample of occlusive material, 5 cm in length, can be secured between totwo test fixtures such that 0.5 cm of material is held within in eachfixture. This test assembly results in a span of 4 cm of occlusivematerial between each fixture face. Thereafter, the fixtured sample canbe placed in the Instron testing machine and compressed at a rate of 30mm/min until the sample buckles. The force recorded at the point ofbuckling is the column strength or pushability number of the occlusivematerial.

In one preparative example, three segments of oxidized foam material,made from small intestine submucosa, each having a pre-compresseddiameter of 16 mm and a length of 5 cm where compressed down to adiameter of 4 mm using a radial compression machine. Thereafter thecolumn strength of each sample was individually determined using anInstron compressive strength testing machine. Each test was executed bysecuring 0.5 cm of each end of each sample within a test fixture suchthat a span of 4 cm of compressed foam material extended between thefaces of the fixtures. The fixed sample was then compressed by theInstron machine at a rate of 30 mm/min and the compressive force wasrecorded. The compressive force at the point each test sample buckledwas recorded as the column strength or pushability number for eachsample. The column strength for each oxidized foam sample was determinedto be 1488.5 kPA, 1849.6 kPA, and 1628.8 kPA, respectively.

Occlusion materials will generally be of sufficient character and/ordimension to achieve occlusion of the desired stretch of vascularvessel, either alone or in combination with other similar or differingdevices. In certain embodiments, the occlusion device (or implantedflowable material) will have a length of at least about 10 cm, and inmany situations at least about 20 cm. Indeed, for preferred occlusionprocedures involving a significant stretch of an artery or vein,occlusion devices having lengths greater than 20 cm will be used.Illustratively, in the occlusion of the greater saphenous vein in humanadolescents or adults, occlusion devices having lengths of at about 40cm or 50 cm can be used. For more information regarding occlusivematerials and methods for manufacturing the same, reference can be made,for example to U.S. Pat./App. Nos. 2003/0051735, 6,444,229, and/orInternational App. Pub. Nos. WO2004/103187, WO2005/053547, and/orWO2005/020847.

Turning now to a discussion of illustrative medical products andprocedures of the invention, the sclerosive or other agents can beconjunctively used with one or more occlusive devices or materialsduring a percutaneous ablation procedure. For example, in certainembodiments, the sclerosive agents and occlusive material can beprovided separately and mixed or cooperatively implanted within apatient during an occlusion procedure. Such cooperative emplacement caninclude injecting or infusing one or more agents within a venous vesselbefore, during, or after implantation of a remodelable material, such asan elongate sponge form material. Alternatively, such conjunctiveplacement can include contacting a remodelable material with asclerosive agent soon before the remodelable material is implantedwithin a patient, such as by soaking the remodelable material in a bathcontaining sclerosive agents. In sill alternative embodiments, one ormore sclerosants can be mixed within a flowable ECM material before thematerial is injected (via syringe) or infused (percutaneously via acatheter) within a venous vessel. The agents can be mixed within theflowable material in preparation for an ablation procedure, or duringthe manufacture of the flowable material (such as by forming theflowable material from an ECM graft material that contains one or moresclerosive agents).

Illustratively, the sclerosive agents may be contained within theocclusive material in any suitable concentration to bring about ahealing response, spasm, constriction, and/or a de-epithelielization inpatient tissue that is in contact with or near the implant location. Inembodiments, such as when a sclerosive solution is directly placedwithin a patient, the sclerosive agent can be carried within an aqueouscarrier solution, such as water, saline, and the like. Illustratively,the concentration of sclerosant in the solution is from about 0.1 volume% to about 10 volume % or greater. In some embodiments the water orsaline can contain from about 2 to about 4 volume % physiologicallyacceptable alcohol, e.g. ethanol. Saline can also be buffered, e.g.phosphate buffered. The pH of the buffer can be adjusted to bephysiological, e.g. from pH 6.0 to pH 8.0, more preferably about pH 7.0.

Sclerosants may also contain additional components, such as stabilizingagents, e.g. foam stabilizing agents, such as glycerol. Furthercomponents may include alcohols, such as ethanol. For more informationregarding sclerosive agents, which may be useful in certain embodimentsof the present invention, reference can be made, for example, to U.S.Pat. No. 6,572,873, which is hereby incorporated by reference in itsentirety.

The concentration of agent used in illustrative occlusive procedures canbe varied depending, for example, on the amount of vessel dilationand/or the type of cooperative emplacement procedure techniques anddevices as can be selected by the physician. Additionally, when dopingan agent into an occlusive construct, higher agent concentrations may beinitially used to impart the agent into the construct than will bepresent within or effectively delivered to the patient at or afterimplantation.

Illustrative dry occlusive products can be formed that contain one ormore sclerosive or other agents throughout one or more regions of theconstruct or within or on one or more surfaces of the construct.Illustratively, such sclerosive agents can be evenly dispersedthroughout the construct, or, alternatively, can be differentiallyconcentrated throughout differing regions or surfaces of the construct,such as for example to form an occlusive construct having highersclerosive agent concentrations at surface areas while having reduced ordiminished sclerosive concentrations at core or inner areas. Such dryform ECM occluders can serve to continually deliver sclerosive agentsinto patient tissue after implantation so as to enhance occlusion andremodeling of the occlusive device. Such occlusive devices can bedeployed in dry form within a patient and thereafter optionally hydratedwith a suitable hydrant, e.g. saline, or in alternative embodiments canbe hydrated before implantation occurs.

Illustrative dry occlusive devices can be formed by contacting anocclusive material with one or more sclerosing agents and thereafterdrying the material so as to form a dry occlusive material that is dopedwith or otherwise contains sclerosive agents. For example, an ECM sheetmaterial can be soaked within a bath containing a sclerosive agent andcan thereafter be rolled and pressed into a mold and thereafterlyophilized (freeze dried) so as to form a substantially unitaryocclusive construct containing sclerosive agents. If desirable, such aswhen the occlusive construct comprises a sponge form ECM material, theconstruct can be compressed or recompressed after lyophilization iscomplete.

While discussions above focus upon occluding the greater saphenous veinvia access at the knee level, the greater saphenous vein may also beaccessed at a higher, e.g. jugular or lower level, e.g. near the ankle.During such access, any or all of the saphenous vein occurring betweenthe ankle and the sapheno-femoral junction may be subjected toocclusion. Other veins in the leg(s) that may be involved in thevaricose vein condition, e.g. spider veins, may also be occluded,alternatively or in addition to the saphenous vein. For example, thelesser saphenous vein, or varicose veins themselves, may be occluded andobliterated in accordance with the invention. Further, other veins orarteries in the leg(s) or elsewhere in the body may be occluded withinthe scope of the present invention.

Percutaneously-conducted occlusion procedures can be performed underlocal anesthesia. In addition, after completion of the procedure, it maybe beneficial to use graduated compression stockings in the occludedarea, for example for a week or more. Compression of the occluded areamay serve to facilitate permanent closure of the occluded vessel, forexample when applied during a remodeling period during which tissueingrowth into the occluded lumen occurs.

Sheaths, dilators, pushers, wire guides and needles used in the presentinvention can all be conventional marketed products or modificationsthereof. For example, sheaths can be formed from PTFE (e.g. Teflon) orpolyamide (e.g. Nylon) material, or a combination of materials such asan assembly including an inner layer of PTFE, a flat wire coil over thePTFE for kink resistance, and a polyamide (Nylon) outer layer to provideintegrity to the overall structure and a smooth surface (e.g. as in theFlexor sheath, Cook, Inc.). Dilators and pushers can be made fromconventional dilator/catheter type materials such as polyethylene,polyamide, stainless steel, polyurethane or vinyl, or any combination ofthese materials. Fittings provided for sheath/dilator assemblies can beconventional elements such as luer locks, and the dilator can have afitting allowing it to be locked to the sheath during insertion andmanipulation. Catheters can be made from conventional materials such aspolyethylene, polyamide, PTFE, polyurethane, and other materials.

Delivery sheaths used in the invention will have a lumen diameter sizedto allow for the introduction of a sufficient amount of occlusionmaterial to occlude the artery or vein of interest. Illustratively, theinner diameter (I.D.) of the final delivery sheath can range from about4 French up to about 40 French.

As is conventional, the distal ends of the catheters, sheaths, dilators,wires or other components, e.g. occlusive constructs, used inpercutaneous procedures can include markers that can be X-ray,sonographically, or otherwise non-invasively visualized to identifytheir location during the procedure. Metallic bands of stainless steel,tantalum, platinum, gold, or other suitable materials, which include adimple pattern, can serve the purpose for both ultrasound and X-rayidentification. As well, distal and/or proximal ends and/or otherlocations on occluder devices of the invention may include markers fornon-invasive imaging, including imageable materials such as thosediscussed above as well as substances that can be applied to ECMs orother collagenous materials, e.g. substances containing tantalum,barium, iodine, or bismuth, e.g. in powder form.

The invention also provides medical kits that include medical productsdescribed herein sealed within medical packaging potentially incombination with other components, such as for example a sheath and/orguidewire. The final, packaged products are provided in a sterilecondition. This may be achieved, for example, by gamma, e-beam or otherirradiation techniques, ethylene oxide gas, or any other suitablesterilization technique, and the materials and other properties of themedical packaging will be selected accordingly.

All publications cited herein are hereby incorporated by reference intheir entirety as if each had been individually incorporated byreference and fully set forth.

While the invention has been illustrated and described in detail in thedrawings and foregoing description, the same is to be considered asillustrative and not restrictive in character, it being understood thatonly the preferred embodiments have been shown and described and thatall changes and modifications that come within the spirit of theinvention are desired to be protected.

1. A medical product for occluding a venous vessel, comprising: aremodelable material configured for deployment within a venous vessel,wherein the remodelable material is effective to promote the ingrowth ofpatient tissue into the lumen of the venous vessel and wherein theremodelable material includes one or more sclerosants that are effectiveto injure the lining of the venous vessel so as to enhance the ingrowthof patient tissue into the remodelable material and promote occlusion ofthe venous vessel.
 2. The medical product of claim 1, wherein theremodelable material comprises a resorbable material or an extracellularmatrix material.
 3. The medical product of claim 2, wherein theextracellular matrix material comprises submucosa, serosa, pericardium,dura mater, peritoneum, or basement membrane.
 4. The medical product ofclaim 3, wherein the submucosa comprises mammalian submucosa.
 5. Themedical product of claim 4, wherein the mammalian submucosa comprisesporcine, bovine, or ovine submucosa.
 6. The medical product of claim 4,wherein the mammalian submucosa comprises intestine submucosa, stomachsubmucosa, urinary bladder submucosa, or uterine submucosa.
 7. Themedical product of claim 6, wherein the intestine submucosa comprisesadult porcine small intestine submucosa.
 8. The medical product of claim1, wherein the one or more sclerosants comprises sodium tetradecylsulfate, morrhuate sodium, ethanolamine oleate, tetradecyl sulfate,tetracycline, glycerin, hypertonic glucose, talc, acetic acid, alcohol,bleomycin, picibanil, ethibloc, deoxycycline polidocanol, sotradecol,ethoxysclerol, or any suitable mixture thereof.
 9. The medical productof claim 2, wherein the extracellular matrix material comprises aflowable material.
 10. The medical product of claim 9, wherein theflowable material comprises from 0.1 to 10 volume percent of the one ormore sclerosants.
 11. The medical product of claim 10, wherein theflowable material comprises from 1 to 3 volume percent of the one ormore sclerosants.
 12. The medical product of claim 11, wherein the oneor more sclerosants comprise polidocanol.
 13. A medical product foroccluding a bodily vessel, comprising: an angiogenic remodelablematerial, wherein the angiogenic remodelable material is configured fordeployment in a bodily vessel of a patient; and one or more sclerosingagents, wherein the sclerosing agents and the remodelable material areconfigured for conjunctive or cooperative use to enhance closure of thebodily vessel.
 14. The medical product of claim 13, wherein the one ormore sclerosing agents are located within the angiogenic remodelablematerial.
 15. The medical product of claim 14, wherein the angiogenicremodelable material comprises a sponge form or foam material.
 16. Themedical product of claim 15, wherein the sponge form or foam materialcomprises an extracellular matrix material.
 17. The medical product ofclaim 16, wherein the sponge form material is dry.
 18. The medicalproduct of claim 13, wherein the angiogenic remodelable materialcomprises an extracellular matrix sheet material.
 19. The medicalproduct of claim 18, wherein the sheet material is folded.
 20. Themedical product of claim 19, wherein the sheet material is fan folded.21. The medical product of claim 18, wherein the sheet material isrolled to form a cylindrical body of overlapping or layered sheetmaterial.
 22. The medical product of claim 21, wherein the overlappinglayers are dehydrothermally bonded.
 23. A method for occluding a venousvessel, comprising: providing a flowable remodelable material that isconfigured for placement within a venous vessel and is effective topromote the ingrowth of patient tissue within the lumen of the venousvessel; providing one or more sclerosive agents that are configured forplacement within the venous vessel in conjunction with the providedflowable remodelable material and wherein the sclerosive agents areeffective to injure the lining of the venous vessel; and locating theprovided flowable material and the provided sclerosive agents within thevenous vessel, wherein the provided flowable material and the providedsclerosive agents cooperate to promote the closure and occlusion of thevenous vessel.
 24. The method of claim 23, wherein the providedsclerosive agents are carried within the provided flowable remodelablematerial.
 25. The method of claim 24, wherein the venous vessel is asaphenous vein.
 26. The method of claim 25, wherein the saphenous veinis a greater saphenous vein.
 27. The method of claim 26, whereinlocating further comprises: providing a cannulated device having aproximal end, a distal end, and a lumen; placing at least the distal endof the provided cannulated device within the venous vessel so as toestablish a communication between the venous lumen and an extracutaneouslocation; and delivering an amount of the provided flowable material andthe provided sclerosive agents into the greater saphenous vein throughthe lumen of the cannulated device.
 28. The method of claim 27, whereindelivering further comprising filling the lumen of the greater saphenousvenous with the provided material so as to close the lumen in at leastone location.
 29. The method of claim 28, wherein the venous lumen iscontinuously filled between a point near the sapheno-femoral junctionand a point near the medial side of the knee.
 30. The method of claim28, wherein the venous lumen is intermittently filled between a pointnear the sapheno-femoral junction and a point near the medial side ofthe knee.
 31. The method of claim 23, wherein locating furthercomprises: mixing the provided flowable material with the providedsclerosive agents; and delivering the mixed materials into the venousvessel.
 32. The method of claim 31, wherein delivering further comprisesinjecting the mixed materials from an extracutaneous location with aneedle and a syringe.
 33. A method for treating varicosities associatedwith venous valve insufficiency, comprising: providing a sponge formremodelable prosthesis that is configured for deployment within thegreater or lesser saphenous vein of a patient, wherein the sponge formremodelable prosthesis includes one or more sclerosive agents; anddeploying the provided sponge form prosthesis within the greater orlesser saphenous vein of the patient so as to provide closure of thevein and treat varicosities associated with venous valve insufficiency.34. The method of claim 33, wherein the sponge form prosthesis has alength of at least about 10 cm.
 35. The method of claim 33, wherein thesponge form prosthesis has a length of at least about 20 cm.
 36. Themethod of claim 33, wherein the sponge form prosthesis has a length ofat least about 30 cm.
 37. The method of claim 33, wherein the spongeform prosthesis has a length of at least about 40 cm.
 38. The method ofclaim 33, wherein the sponge form prosthesis has a length of at leastabout 50 cm.
 39. The method of claim 33, wherein providing furthercomprises applying the one or more sclerosive agents to the sponge formremodelable prosthesis under the supervision of a medical doctor. 40.The method of claim 33, wherein providing further comprises applying theone or more sclerosive agents to the sponge form remodelable prosthesisas a preparative step in a percutaneous procedure.
 41. A medical kit,comprising: a product according to claim 1 enclosed in sterile medicalpackaging.